Stimulation of the tibial nerve—a randomised trial for urinary problems associated with Parkinson’s—the STARTUP trial

Abstract Background non-motor symptoms such as bladder dysfunction are common (80%) in people with Parkinson’s increasing the risk for falls with a negative impact on health-related costs and quality of life. We undertook STARTUP to evaluate the clinical and cost-effectiveness of using an adhesive electrode to stimulate the transcutaneous tibial nerve stimulation (TTNS) to treat bladder dysfunction in people with Parkinson’s disease (PD). Study design, materials and methods: STARTUP was a parallel two-arm, multi-centre, pragmatic, double-blind, randomised controlled trial. Each participant attended one clinic visit to complete consent, be randomised using a computer-generated system and to be shown how to use the device. The trial had two co-primary outcome measures: International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and the International Prostate Symptom Score (IPSS). These were completed at baseline, 6 and 12 weeks. A bladder frequency chart and resource questionnaire were also completed. Results two hundred forty two participants were randomised. About 59% of participants were male, the mean age was 69 years and mean time since diagnosis was 6 years. Questionnaire return rate was between 79 and 90%. There was a statistically significantly lower score in the active group at 6 weeks in the IPSS questionnaire (mean difference (Standard deviation, SD) 12.5 (6.5) vs 10.9 (5.5), effect size −1.49, 95% CI −2.72, −0.25). There was no statistically significant change in any other outcome. Conclusion TTNS was demonstrated to be safe with a high level of compliance. There was a significant change in one of the co-primary outcome measures at the end of the treatment period (i.e. 6 weeks), which could indicate a benefit. Further fully powered RCTs are required to determine effective treatments.


Background
Parkinson's disease (PD) is characterised predominantly by motor complaints, such as slow and restricted walking, rigidity and tremor. The reported prevalence of lower urinary tract symptoms (LUTS) in people with Parkinson's (PwP) ranges from 38 to 71% and is largely manifested by storage/overactive bladder (OAB) symptoms, which include nocturia (>60%), urinary urgency (33-54%), daytime frequency (16-35%) and urinary incontinence (26-28%; [1]). The latter may be in part functional if immobility, cognitive impairment or poor manual dexterity complicates the situation. LUT symptoms have been shown to exacerbate the risk for falls, fractures and decreased quality of life [2].
Current treatments for LUTS in PwP are limited, with very few high quality studies on effectiveness. It is likely that levodopa and other Parkinson's medication affect bladder function; however, studies evaluating the effects of these medications on micturition have produced conflicting results [1]. Currently, PwP may be offered advice on fluid intake and behavioural treatment such as habit training or timed voiding with or without pelvic floor muscle training, but the evidence base supporting these techniques is limited. Anticholinergics are generally used as a first-line treatment for OAB symptoms. However, it is important to balance the therapeutic benefits of these drugs with the reported adverse effects, such as dry mouth, constipation, increased risk of higher post-void residuals and their potential effect on cognitive function, and caution in prescribing is advised [3,4]. Intravesical injection of botulinum toxin into the detrusor is sometimes considered in PwP and has been described in four small studies to date, which reported some improvement in symptoms [5][6][7][8]. For the reasons discussed, there is a need to explore options that are non-invasive and associated with minimal side effects.
The tibial nerve is a mixed nerve containing sensory and motor fibres of L4-S3, and it originates from the same segments of the spinal cord as the innervation to the bladder, pelvic floor and rectum. There is some evidence that stimulating this nerve with low-frequency pulses at a tolerable intensity can potentially treat OAB-related symptoms [9][10][11]. Although the exact mechanism is not yet fully understood [12][13][14][15], this stimulation is thought to increase inhibition of the spinothalamic neurons within the spinal cord, reducing firing input to the pontine micturition centres (PMC) and inhibiting the information facilitated by those nerves to the bladder [16][17][18][19][20]. Percutaneous stimulation (using a small gauge needle) or transcutaneous stimulation (using a sticky electrode just behind the medial malleolus) are the primary methods of delivering the stimulation produced by a small hand held unit.

Objectives
The STARTUP trial was a fully powered two groups (Intervention vs Placebo) double-blind RCT to assess if transcutaneous tibial nerve stimulation (TTNS) was an effective therapeutic option for the treatment of OAB symptoms in PwP.

Methods
A published protocol is available for the trial [21]. Participants were recruited from 12 UK community outpatient care settings where PD care was usually provided. Additional help with recruitment was provided by Parkinson's UK, who promoted the trial on their website. Clinicians delivering the intervention at the sites were trained by the STARTUP trial team in the trial processes and intervention delivery.
Following the provision of study information participants attended for one trial visit where inclusion/exclusion criteria were checked, and questions were answered prior to them giving informed consent.

Inclusion criteria
• Patients of >18 years of age with a diagnosis of Parkinson's and self-reported problematic LUT symptoms. • Capacity to consent and comply with the protocol. • Stable Parkinson's medication for 3 months. • Participants who were treatment naïve, failed or continuing treatment with antimuscarinic medication (group allocation was minimised to account for these groups). • Patients who were being or had been treated for benign prostatic hyperplasia or prostate cancer could be included at the discretion of the PI. • Patients taking medications such as alpha-blocker medicines could be included at the discretion of the PI. • Patients who were being or had been treated for cancer (e.g. urological cancer) could be included on an individual basis at the discretion of the PI.

Exclusion criteria
• Pacemaker or implanted electrical device, including deep brain stimulation. • Ulceration or broken skin in area of pad placement.

Randomisation
Group allocation was carried out remotely via a web-based automated application provided by the clinical trials unit in Aberdeen. The allocation ratio was 1:1 with minimisation by (i) severity of urinary symptoms, using the International Prostate Symptom Score (IPSS; [22,23]), at baseline and (ii) the status on antimuscarinic medication, i.e. treatment naïve, failed or continuing such treatment. Participants and those who undertook data input and analysis were blind to group allocation.

Sample size
Please see protocol for the full justification of our sample size [21]. Monitoring of accruing data indicated better retention rates but greater variance in the outcome measures than had been originally assumed. The original sample size of 208 [21] was revised to 236 to allow for retention of 85% and standard deviation (SDs) of 5.5 and 6.5 for International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) and IPSS respectively. This amendment was approved in November 2019 (GN18RE170 REC reference: 18/ES/00420 and by our Trial Steering Committee).

Outcome measures
Participants completed questionnaires at baseline (pretreatment), 6 and 12 weeks. The trial had two co-primary outcome measures: ICIQ-UI SF [24] and the IPSS [22,23], which are validated for use in males and females.
The ICIQ-UI SF assesses the impact of symptoms of incontinence on quality of life and outcome of treatment. It consists of four questions measuring frequency of urinary incontinence (UI), amount of leakage, overall impact of UI and when leakage occurs. The total score ranges from 0 to 21 with higher values indicating increased severity of symptoms [24].
The IPSS is based on the answers to seven questions concerning OAB symptoms. Questions 1-7 refer to: incomplete emptying; frequency; intermittency; urgency; weak stream; straining and nocturia. Question eight refers to the patient's perceived quality of life. Each question is assigned points from 0 to 5 indicating increasing severity of the particular symptom. The total score ranges from 0 to 35 (asymptomatic to very symptomatic). Patients can be tentatively classified: 0-7 = mildly symptomatic; 8-19 = moderately symptomatic and 20-35 = severely symptomatic [22,23].
Participants also completed a 72-h Bladder diary recording micturition frequency, leakage episodes and urgency.
Resource use relating to bladder symptoms was also monitored at the 6 and 12 week time-points, with questions relating to visits to the doctor/nurse/hospital, medications bought/prescribed and purchases such as continence pads. An economic evaluation considered the cost-effectiveness of providing TTNS for PwP and OAB symptoms compared with placebo from a health sector perspective.
Participant experience and protocol fidelity was assessed at 6 weeks in a brief quantitative exit questionnaire. All diaries and questionnaires were returned to the trial office in a reply-paid envelope.

Intervention
Following randomisation participants were shown how to use the device according to group allocation. The treatment protocol developed by Amarenco et al. [27] was followed. Participants allocated to the intervention group were asked to place the self-adhesive surface electrode on either leg, 2cm behind the medial malleolus (inside of ankle) and the positive electrode 10-cm proximal to it. The stimulation frequency was delivered at a fixed frequency of 10 Hz and pulse width of 200 μs in continuous mode. Setting of the intensity level of stimulation current (range 0-50 mA) was guided by the motor (flexion of the big toe) or sensory response (paraesthesias over the sole).
Participants randomised to the placebo group were asked to place the electrodes on the lateral side of the leg (outside of ankle) thus avoiding the tibial nerve and relevant cutaneous nerves. The stimulation current was pre-set at 2 Hz, and participants were advised to turn the unit up until they felt a slight sensation and then turn it down to 2 mA.
The clinician set the parameters and locked the TTNS unit to ensure participants were unable to change the settings or delete data. All equipment and an instruction booklet were issued to the participant to take home. All participants were advised to use the stimulator for two 30-min sessions per week for 6 weeks. The stimulation unit recorded how often and for how long the participant used it during the 6 weeks of intervention. This usage information was downloaded when the unit was returned to centre staff.
Participants were phoned weekly to ascertain fidelity. A final follow-up call was made at week 12 to ascertain the success or otherwise of blinding.

Results
A total of 242 participants were randomised, 121 in the intervention group and 121 to receive placebo TTNS. The mean age was 69 years (SD 8.6), 59% (n = 121) of participants were male and median time from diagnosis was 5 years (interquartile range, IQR 6.3). The two randomised groups were comparable at baseline (Table 1 and Figure 1). Follow-up questionnaire return rates were 93% at baseline, 88% at 6 weeks and 81% at 12 weeks. Attrition was low and similar in both groups. At 6 weeks, eight participants had withdrawn, four were lost to follow-up and one had died. At 12 weeks there was one further withdrawal and seven lost to follow-up.
The statistical analysis used an intention to treat approach. The primary outcome analysis indicated there was no significant difference between the two groups in the severity of ICIQ-UI SF score at any time-point ( Table 2). Analysis of the co-primary outcome measure indicated that IPSS was statistically significantly lower in the active TTNS group at 6 weeks (mean difference (SD) 12.5 (6.5) vs 10.9 (5.5), effect size −1.49, 95% CI −2.72, −0.25). A difference of 3 points is thought to be clinically meaningful [23], hence this was not clinically significant. There was no statistically significant difference at 12 weeks.
Analysis of secondary outcomes (Appendices 1 and 2, Supplementary data are available in Age and Ageing online) indicated there were no significant differences between groups in frequency of micturition (bladder diary) or quality of life measures (SF-Qualiveen, PDQ-8). The number of daily micturition episodes were ∼9 per day during all three phases. There was a small but not significant difference in the number of daily urgency episodes and the number of daily leakage episodes in favour of the active TTNS group.
The participant experience of using the TTNS device was positive with 90% saying it was easy to use and 80% saying they were willing to continue using the device. Recorded use of the stimulator reported an average use of 5.7 (SD 1.5) hours in each group per week (recommended 6 h per week) with complete usage of unit i.e. 6 h in over 65% of participants in each group. About 52% of the intervention group reported that they thought they were in the intervention group and 73% of the control group thought they were in the control group. There were no related adverse events.

Subgroup analysis/sensitivity analysis
Post-hoc subgroup analyses were undertaken for the two primary outcomes using: age (<65 and +65); gender; antimuscarinic drug use status (naïve, continuing and failed) and symptom severity.
There were no significant subgroup interactions. The age subgroup analysis showed some difference in IPSS at 6 weeks, with those ≥65 years showing greater improvement than <65 years, but this was not significant at the stricter level of 1% required for this analysis.

Cost-effectiveness analysis
Resource use questionnaires were used to calculate average NHS resource use and data on the cost of the intervention and placebo intervention were collected. Table 3 details the number of appointments attended by those in each group and the unit cost and source used in the cost-effectiveness analysis. The cost of the intervention, including equipment and staff costs, was calculated as £148.

Stimulation of the tibial nerve
The average cost for each group (over 12 weeks) for the placebo and intervention groups, calculated as £216 and £212, respectively. These total costs included NHS appointments, pad usage, medication and trial related costs.
The differences in scores from the primary outcome measures and average resource use (NHS and trial costs) were   combined to compare the costs and benefits between the placebo and intervention groups. NHS resource use was similar in both groups. Where there was improvement in the primary outcome and an additional cost, the added cost per one-point reduction in urine leakage (ICIQ-UI SF) and in LUT dysfunction (IPSS) was calculated (Table 4).
Over the 12 weeks, the intervention group showed an improvement in the primary outcome measures with lower resource use.
In reality, it is unlikely that those in the control group would receive any intervention hence a sensitivity analysis was run, which excluded the placebo intervention cost but included the NHS resource use for the placebo group. This resulted in an additional cost for the intervention. Full results are shown in Appendix 3, Supplementary data are available in Age and Ageing online.

Discussion/Conclusion
In this double-blind RCT a significantly lower (better) total IPSS score was found at 6 weeks in the intervention group compared with the control group, although the difference fell short of the threshold for clinically meaningful improvement, defined as 3 points. There was no significant difference between groups in any other outcome measures at any time-point. The subgroup analyses did demonstrate a trend towards greater benefit in men over 65 and this was also cost-effective with lower cost and improved health for the intervention group, but this was not statistically significant.
TTNS treatment was shown to be safe and associated with high compliance and willingness from patients to continue the treatment beyond the trial period.
Unlike motor disorders, bladder dysfunction is nonresponsive to levodopa, a precursor of central dopamine, suggesting this dysfunction occurs through complex pathophysiology [28]. Despite its impact on the quality of life of PwP we believe that this is the first double-blind, RCT relating to bladder management [29].
TTNS is a form of peripheral neuromodulation targeted towards symptom relief of OAB and urge urinary incontinence. As well as the possible modulation of the neuronal signals from the spinal cord to the PMC neuromodulation may also have supra-spinal effects, which have been investigated in human studies by studying somatosensory evoked potentials before and after percutaneous tibial nerve  stimulation (PTNS) and sacral neuromodulation. The results showed alterations in somatosensory evoked potential [15,30]. This means that stimulation at the tibial nerve results in modifications of synaptic efficiency through the somatosensory pathway, providing information on the function of somatosensory cortical structures at the spino-thalamic level. Whether such stimulation can influence the effect PD has on bladder control is unknown. Potentially PTNS may be a more accurate and more intense type of stimulation, yet studies have demonstrated equal effectiveness; a study with 68 participants with overactive detrusor persisting after first-or second-line treatments in a non-superiority trial reported no difference in efficacy between PTSN and TTNS [31]. The protocol of the intervention we used was selected from previous studies, the frequency of twice a week was selected following feedback from PwP in what was acceptable to them.
To minimise the risk of performance bias the intervention and training were standardised as far as possible.
Identical equipment was used in a similar pattern over the 6-week intervention period for both groups with the patient or carer being unaware of group allocation. The outcome measures were entered by trial ID number only. The only differences between groups were the electrode position on the ankle (medial in the TTNS group, lateral in the sham group) and intensity of stimulation (highest comfortable intensity > 10 mA in the TTNS group; 2 mA in the sham group). About 72% of the sham group and 51% of the intervention group guessed their group allocation correctly at the end of the intervention period. However, both groups had similar levels of adherence as recorded on the hidden treatment timer, and both reported similar levels of wanting to continue with the use of the device.
No questionnaires have been specifically validated in PD patients and bladder dysfunction. A review published since the trial inception concluded that the IPSS may not be sensitive to change in PwP [32]. The change in score of the IPSS at 6 weeks was 2.4 points but once the results are adjusted to take account of the covariates it was further reduced (1.49). Our sample size justification was based on a study by Ruffion et al. [23] with 150 patients with LUTS associated with benign prostatic hyperplasia, who established the mean absolute minimal important difference of 3 points [23]. Although this was a different population a paper by Ragab and Mohammed [33] identified that the total IPSS symptoms score significantly correlated with quality of life in PwP. The authors stated that 'It is well known that the IPSS questionnaire is not specific for evaluating prostatism in men. This also implies that the IPSS is useful in evaluating voiding dysfunction in neurodegenerative diseases in both men and women' [34][35][36]. However further research is required to validate such an outcome measure in PwP. Pavy-Le Traon (32) continue to say that the IPSS does not measure some key problems encountered in PD e.g. incontinence.
A limitation of the study was that some characteristic data regarding the PD patients was not collected, which makes it more difficult to generalise and contextualise findings.

Message
In summary, TTNS was demonstrated to be safe but, despite a high level of compliance, the evidence of effectiveness for TTNS from this fully powered RCT was limited to a statistically significant difference between groups at 6 weeks, which was not clinically significant [23]. The interest shown by PwP in taking part in our research would clearly indicate a lack of effective interventions. Further fully powered RCTs are required to establish treatments and a clear pathway to help improve the quality of life of PwP by improving their LUTS symptoms.
Supplementary Data: Supplementary data mentioned in the text are available to subscribers in Age and Ageing online.